Abstract (Project Summary) The overall goal of the proposed project is to elucidate neurobehavioral mechanisms underlying the relationships between a history of childhood sexual abuse (CSA) and alcohol and other substance use outcomes in women. Women with CSA history have earlier onset of alcohol misuse and higher rates of alcohol use disorders, even after controlling for family background factors influencing both CSA exposure and problem drinking, such as family history of alcoholism. Converging evidence suggests that CSA and its consequences for brain development may constitute a distinct etiological pathway to alcoholism in women. However, neural, cognitive, affective, and behavioral processes and mechanisms underlying the link between CSA and alcohol abuse are not well understood. Existing research on neurobehavioral consequences of CSA have typically relied on small samples and insufficiently matched control groups limiting control for family-level confounding factors and causal inferences. The proposed study seeks to address these gaps in knowledge and methodological challenges by utilizing a unique resource consisting of several large, well-characterized, longitudinal samples and implementing a model-driven set of experimental paradigms to test the hypothesis that problem drinking in CSA+ women is mediated by biased affective processing and dysfunction in cognitive control, leading to dysregulated affect and, consequently, coping motives for drinking. The proposed studies are strongly grounded in the current theories of addiction and supported by preliminary findings from our laboratory. Young adult women with a history of early CSA (n=80) and propensity score-matched controls (n=120, including 40 CSA- co-twins from CSA-discordant MZ twin pairs) will participate in a laboratory session involving face-to-face interviews, behavioral and cognitive testing, and the recording of quantitative EEG and ERPs in several behavioral paradigms. The following Specific Aims will be pursued: 1) to elucidate behavioral and psychophysiological mechanisms underlying the relationship between CSA, alcohol, and other substance use outcomes in women, 2) to examine alcohol cue reactivity (ACR) in CSA+ and CSA- women and its relationship with drinking motives and problem drinking, and 3) to determine whether observed differences associated with CSA represent consequences of abuse rather than pre-existing vulnerabilities by using the cotwin control design. In summary, the proposed project is aimed at bridging important gaps in knowledge and will be one of the first well-powered and well-controlled inquiries into the neurobehavioral pathways and mechanisms underlying an important etiological pathway to alcoholism in women. Several aspects of the proposed research are particularly novel: the use of propensity score matching and discordant twin analyses to control for potential confounding variables, focus on a specific etiological pathway to alcoholism in women; and explication of neurobehavioral mechanisms underlying the link between CSA and alcohol problems.